Diabetes mellitus (or diabetes) is one of the most prevalent diseases in the world today. Diabetes patients have been divided into two classes, namely type I or insulin-dependent diabetes mellitus and type II or non-insulin dependent diabetes mellitus (NIDDM). NIDDM accounts for approximately 90% of all diabetics and is estimated to affect 12-14 million adults in the U.S. alone (6.6% of the population). NIDDM is characterized by both fasting hyperglycemia and exaggerated postprandial increases in plasma glucose levels. NIDDM is associated with a variety of long-term complications, including microvascular diseases such as retinopathy, nephropathy and neuropathy, and macrovascular diseases such as coronary heart disease. Numerous studies in animal models demonstrate a causal relationship between long term hyperglycemia and complications. Results from the Diabetes Control and Complications Trial (DCCT) and the Stockholm Prospective Study demonstrate this relationship for the first time in man by showing that insulin-dependent diabetics with tighter glycemic control are at substantially lower risk for the development and progression of these complications. Tighter control is also expected to benefit NIDDM patients.
Current therapies used to treat NIDDM patients entail both controlling lifestyle risk factors and pharmaceutical intervention. First-line therapy for NIDDM is typically a tightly-controlled regimen of diet and exercise since an overwhelming number of NIDDM patients are overweight or obese (67%) and since weight loss can improve insulin secretion, insulin sensitivity and lead to normoglycemia. Normalization of blood glucose occurs in less than 30% of these patients due to poor compliance and poor response.
Over the years, significant effort has been brought to bear towards developing inhibitors against fructose-1,6-bisphosphatase (FBPase), as novel therapeutics for the treatment of type-2 diabetes. Inhibitors have been searched for because FBPase is a critical enzyme involved in the control of gluconeogenesis.1,2 In type-2 diabetes, the enzymatic control of the gluconeogenesis pathway is compromised, thus allowing the production of excessive amounts of glucose resulting in the elevated blood glucose levels characteristic of the disease. In normal individuals, when blood glucose levels are high there is a corresponding increase in the concentration of fructose 2,6-bisphosphate, a highly potent competitive inhibitor of FBPase. The activity of FBPase can also be inhibited allosterically by AMP, thus providing alternate sites for the development of potent therapeutics.
FBPase is a homotetrameric enzyme that exists in either an active (R) or an inactive (T) conformational state.3 Regulation of enzymatic activity involves changes in conformation of the quaternary structure between the R and T states. Metal cations, fructose 1,6-bisphosphate, and fructose-6-phosphate stabilize the R state, while AMP acts as the negative allosteric regulator of FBPase activity, inducing the conformational change from the R to T state. It has also been found that fructose-2,6-bisphosphate synergistically increases the binding of AMP.2 
As a drug target, there are three possible sites of inhibition: the active site, which binds the substrate fructose-1,6-bisphosphate (FBP), the allosteric site which binds AMP, and a ‘novel allosteric site’, at the intersection of the two-fold axis.
To date, considerable research has been focused on designing small molecule inhibitors of FBPase. In 2001, Wright et al.4 reported a novel series of anilinoquinazolines as allosteric inhibitors of FBPase. These inhibitors were identified through screening a library of compounds known to be enzyme inhibitors that compete with AMP and/or ATP, and they were eventually found to bind at the ‘novel allosteric site’. Other small-molecule inhibitors include MB05032.5 The actual drug candidate, CS-917, is a pro-drug version of MB05032, in which the charged phosphate is protected by groups that are removed in vivo.5 MB05032 binds to the allosteric site of human FBPase and is competitive with the binding of AMP. Another class of inhibitors identified by a high-throughput screen (HTS) is a group of benzoxazole-2-benzenesulfonamides reported by Geldern et al.6 
Millions of people have Type 2 diabetes. Efforts are underway by various groups to develop small molecule compounds that can help to combat this disease. Many different targets have been identified and many different approaches are being investigated. Since the enzyme FBPase naturally controls the formation of sugar, it has been a target for the development of anti-diabetic drugs. However, most of these possible drug candidates have not been successfully passed through all of the stages of drug testing.
There is thus an ongoing need to create new compounds that can be used to fight diabetes. This invention answers that need.